Immunological memory is the ability of the immune system to respond with greater vigor upon re-encounter with the same pathogen and constitutes the basis of vaccination against infectious diseases. A better understanding of immunological memory is critical for the rational design of vaccines. This proposal examines the mechanisms that regulate the generation and maintenance of CDS T cell memory to viruses. CDS T cells play a critical role in controlling viral as well as intracellularbacterial and parasitic infections and are also of importance in immunity against tumors. The specific aims of this proposal are as follows: 1. To characterize the global reprogramming of gene expression that accompanies memory CDS T cell differentiation using DNA microarray technology. A global view of changes in expression of genes with known functions could provide a vivid picture of the biochemical mechanisms that produce accelerated response to antigen and longevity in memory CDS T cells. With the recent breakthroughs in our ability to isolate pure populationsof antigen specific naive, effector and memory CDS T cells, and the development of DNA microarray technology, it is now possible to monitorgenome-wide expression in antigen specific CDS T cells. 2. To understand the mechanisms that regulate homeostatic proliferationand maintenance of memory CDS T cells. It is now well established that memory T cells undergo a slow proliferativerenewal. The experiments proposed in this aim will attempt to characterize the nature of this homeostatic proliferation and to understand how it is regulated. We feel that understandingthe regulation of homeostatic proliferation is the key to understanding memory T cell maintenance and the studies proposed in this aim should provide insight into this important issue. 3. To compare on a per cell basis the ability of memory CDS T cells induced by different antigen delivery systems to confer protective immunity. Protective immunityis the essence of immunological memory and this aim addresses a crucial biological question about memory T cells;namely, are memory CDS T cells induced by different vaccine regimens equally good at protective immunity against viral infection. The fact that different vaccines generate different numbers of memory CDS T cells has been long appreciated and is usually considered to be the primary, if not the sole reason, for varying levels of protective immunity induced by different vaccines. The qualitative aspects of vaccine induced memory T cells have nor received much attention. The experiments proposed in this aim will address this specific issue. The goal of this aim is to determine what type of vaccines will generate the mosi;optimal memory CDS T cells.